RHIZOMELIC CHONDRODYSPLASIA PUNCTATA IS A PEROXISOMAL PROTEIN TARGETING DISEASE CAUSED BY A NONFUNCTIONAL PTS2 RECEPTOR

Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive disease characterized clinically by a disproportionately short stature primarily affecting the proximal parts of the extremities, typical dy smorphic facial appearance, congenital contractures and severe growth and mental retardation. Although some patients have single enzyme defi ciencies, the majority of RCDP patients (86%) belong to a single compl ementation group (CG11, also known as complementation group I, Amsterd am nomenclature(1)). Cells from CG11 show a tetrad of biochemical abno rmalities: a deficiency of i) dihydroxyacetonephosphate acyltransferas e, ii) alkyldihydroxyacetonephosphate synthase, iii) phytanic acid alp ha-oxidation and iv) inability to import peroxisomal thiolase. These d eficiencies indicate involvement of a component required for correct t argeting of these peroxisomal proteins. Deficiencies in peroxisomal ta rgeting are also found in Saccharomyces cerevisiae pex5 and pex7 mutan ts(2-6), which show differential protein import deficiencies correspon ding to two peroxisomal targeting sequences (PTS1 and PTS2). These mut ants lack their PTS1 and PTS2 receptors, respectively. Like S. cerevis iae pex7 cells, RCDP cells from CG11 cannot import a PTSZ reporter pro tein(7). Here we report the cloning of PEX7 encoding the human PTSZ re ceptor, based on its similarity to two yeast orthologues. All RCDP pat ients from CG11 with detectable PEX7 mRNA were found to contain mutati ons in PEX7. A mutation resulting in C-terminal truncation of PEX7 cos egregates with the disease and expression of PEX7 in RCDP fibroblasts from CG11 rescues the PTSZ protein import deficiency. These findings p rove that mutations in PEX7 cause RCDP, CG11.